Cancer health disparities among African Americans are increasing. Vitamin D is suspected to play a role in several cancers and other chronic conditions with a higher incidence among African Americans. The actions of vitamin D are mediated through the vitamin D receptor (VDR). VDR acts to promote or prevent downstream gene signaling through vitamin D response elements (VDRE) located in the promoter region of vitamin D-responsive genes. Epidemiologic studies are limited by the unknown function of VDR SNPs, and their relation to variants within VDRE that may differ by race/ethnicity. Epidemiologic research has focused on VDR, although other genes within the metabolic pathway are likely important. We have identified a novel polymorphic variant occurring in one VDRE of 24-hydroxylase, the main catabolic enzyme of vitamin D and most highly VDR-inducible gene in a sample of healthy African Americans (15% population prevalence). Using a gel-shift assay, we have demonstrated that this VDRE polymorphism eliminates VDR binding. It is likely that unidentified SNPs occur in other VDRE genes. Therefore, we propose the following specific aims: 1) Conduct SNP discovery within and near Vitamin D Response Elements (VDRE) located in the promoter region of genes involved in vitamin D metabolism (VDR, CYP24A1 and CYP3A4);2) Molecularly characterize VDRE polymorphic variants alone and in combination with VDR-short and VDR-long polymorphic variants;and 3) Epidemiologically characterize VDRE polymorphic variants alone and in combination with VDR-short and VDR-long forms in relation to serum vitamin D. We will test the hypothesis that VDR and VDRE genotypes are independently associated with serum vitamin D, adjusting for age, sex, sunlight exposure, season, dietary intake, genetic ancestry, skin reflectance (melanin index). By understanding the independent contribution of VDR/VDRE genetic variants, genetic ancestry, and environmental contributors to serum vitamin D levels, this research will assist important public health efforts to reduce vitamin D deficiency and health disparities related to vitamin D. We will also advance the understanding of the influence of gene polymorphisms and improve the interpretive power of epidemiologic studies by increasing collaborative efforts between molecular biologists, biochemists, and epidemiologists in our Cancer Health Disparities and Vitamin D Working Group. Career Goal: Develop a thriving molecular epidemiologic research program in an environment of strong interdisciplinary exchange. Dr. Wilson is a former post-doctoral research fellow with the NCI Division of Cancer Epidemiology and Genetics and is currently a tenure-track faculty member at Penn State. This proposal is consistent with the NIH Road Map's call for interdisciplinary research teams and NCI priorities to reduce cancer disparities and advance molecular epidemiology.